During an inflammatory response, injuried tissues release cytokines that trigger the expression of P-selectin followed by E-selectin on the endothelium. The selectins then interact with Sialyl Lewis X (sLex), a tetrasaccharide of the terminal unit of surface glycoproteins and glycolipids. This interaction between the selecting and sLex leads to leukocyte "rolling", followed by protein-protein interactions (integrins CD 11/18, ICAM-1 ligand) causing firmer adhesion and eventually extravasation of leukocytes into the endothelium. Blocking the sLex/selectin interactions at an early stage of the inflammatory cascade, especially the P-selectin-ligand interactions, is an effective way of treating acute and perhaps chronic inflammatory diseases (Buerke et al., J. Clin. Invest. 1994, 1140; Giannis et al., Angew. Chem. 1994, 106, 188).
Though sLex is being clinically evaluated as a drug candidate for the treatment of reperfusion injury, it can only be administered by injection with a high dose, as it binds the selectins weakly and is orally inactive and unstable in the blood. sLex has, however, served as a useful lead for the design of simpler and better low molecular weight compounds as selectin antagonists. On the basis of the crystal structure of E-selectin, NMR studies of the conformations of sLex in solution and bound to E-, P- and L-selectin (Ichikawa et al. J. Am. Chem. Soc. 1992, 114, 9283; Cooke et al. Biochemistry 1994, 33, 10591; Scheffler et al. Angew. Chem. 1995, 107, 2034; Angew. Chem. Int. Ed. Engl. 1995, 34, 1841; Poppe et al., J. Am. Chem. Soc. 1997, 119, 1727), and the structure activity studies of sLex derivatives and mimetics (Bradley et al. Glycobiology, 1993, 3, 633; Stahl et al. Angew. Chem., 1994, 106, 2186, Angew. Chem. Int. Ed. Engl., 1994, 33, 7096; DeFrees et al., J. Am. Chem. Soc., 1993, 115, 7549), the crucial functional groups in space required for the sLex epitope binding to the selectins have been elucidated. Using this recognition model, a vast number of structurally diverse low molecular weight compounds as sLex mimetics have been prepared. Some of them exhibit equal or higher affinity towards the selectins than sLex (Wu et al. Angew. Chem. 1996, 108, 106; Angew. Chem. Int. Ed. Engl. 1996, 35, 88; Lin et al., J. Am. Chem. Soc. 1996, 118, 6826; Wong et al. ibid., 1997, 119, 8152; Kolb et al., Chem. Eur. J., 1997, 3, 1571) as shown in FIG. 1.
Recently, interest in solid phase synthesis has increased dramatically, mainly due to the excitement emerging from the concept of combinatorial chemistry as a powerful tool for the discovery of biologically active compounds and for lead optimization (Gallop et al. J. Med. Chem. 1994, 37, 1233; Gordon et al., ibid. 1994, 37, 1385; Fruchtel et al., Angew. Chem. 1996, 108, 19; Angew. Chem. Int. Ed. Engl. 1996, 35, 17; Balkenhohl et al., ibid. 1996, 108, 2436; ibid. 1996, 35, 2288; Combinatorial Peptide and Nonpeptide Libraries, Ed. G. Jung, VCH, Weinheim, 1996; Lam et al., Chem. Rev., 1997, 97, 411; Nefzi et al.; Ostresh et al., ibid. 1997, 97, 449). In particular, the multiple or parallel synthesis of individual compounds on solid phase is considered to be a promising approach to rapid optimization of previously identified lead structures.
What is needed are new strategies applicable to the parallel and/or combinatorial synthesis of a designed library of O- and C-C-fucopeptides structurally related to 2, and analogs nearly as active or more active as SLex against E-selectin.